Summary Alzheimer's disease (AD) is the most common cause of dementia that affects approximately 5.3 million people in the USA today. The incidence of AD increases dramatically with age, affecting ~7% of people by the age of 65 years and 45% by the age of 85 years. The cost of caring and treating AD patients today is ~$172 billion, but it is predicted to rise dramatically by the year 2050 because of an anticipated four-fold increase in AD. AD is clinically distinguished by severe loss of both memory and cognition, and pathologically by massive neuron loss combined with increased deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT) in the brain. Amyloid plaques are composed principally of small proteolytic fragments of the amyloid precursor protein (APP), whereas NFT are composed of abnormally modified forms of tau protein. There is considerable debate as to the exact cause(s) of AD, however it is generally agreed that the two lesions, the plaques and tangles, are somehow inextricably linked to the disease. An understanding of how APP is processed to generate the potentially toxic amyloid ? fragments (A?) that accumulate in plaques has become a central focus of much AD research. These studies have revealed that processing of APP is complex, but, for simplicity sake, it has been divided into the non- amyloidogenic and amyloidogenic pathways. Currently, there is no effective treatment that delays or prevents AD. Part of this problem might be that researchers have focused on solutions that might be too downstream of the instigating molecular insults. The foundation of this proposal rests on the increasing evidence that disturbances in protein homeostasis, arising from defects in protein quality control systems, play in many neurodegenerative disorders. Our hypothesis is that malfunction of ubiquitin ligases that function as key regulators of protein quality control systems cause abnormalities in APP processing that is directly linked to AD pathogenesis. Accordingly, we propose that the identification of ubiquitin ligases that alter APP processing might provide new therapeutic targets for preventing and treating AD. However, the human genome contains several hundred ubiquitin ligases and the challenge is to find which ones regulate APP processing and potentially AD pathogenesis. We propose a practicable strategy to screen and identify ligases that regulate APP processing. Indeed we provide preliminary data that suggests it is not only possible to find these ligases, but that some ubiquitin ligases might be beneficial by shifting APP processing to a predominantly non-amyloidogenic pathway, whereas others might be detrimental and shift APP processing in the opposite way, to the amyloidogenic pathway. We articulate the rationale and research strategy for why, and how investigation into these ligases could provide novel therapeutic opportunities to treat AD.